Lung cancer is the second most common cancer found in both men and women. It is estimated there will be roughly 228,000 new lung cancer cases this year, and nearly 30% of those patients will have mutations in the K-Ras pathway. This type of mutation makes the cancer more aggressive and difficult to treat. K-Ras is a gene that regulates cell signaling in an “on-off” manner, leading to normal cell growth and division. Mutations that occur in the K-Ras gene cause the protein to ignore any “off” signals that it receives, which results in unchecked cell growth. This is why researchers have been investigating areas in this pathway as possible therapeutic targets. For example, in melanoma, therapies that target the B-Raf mutation, an upstrem protein kinase in the RAS-ERK pathway, have led to a positive patient response. Researchers at Moffitt Cancer Center are hoping to change that. These studies will help determine if modulation of the immune microenvironment along with tumor signaling is a viable treatment strategy for lung cancer patients with K-Ras mutations and potentially other mutations that rely on MEK signaling. In a new study published in Cancer Research, the team discovered a new treatment approach that may help this group of patients.

Moffitt researchers believe the MEK kinase, part of the RAS-ERK pathway, can be a possible target for lung cancer treatment. Through a battery of experiments with cell lines, animal models and drug screenings, they found that lung cancer cells treated with the MEK inhibitor trametinib in combination with the cytokines TNF-alpha and IFNγ resulted in substantially more cell death than treating with a MEK inhibitor alone. TNFα was identified in the 1970s as Tumor Necrosis Factor but initial enthusiasm for using it in cancer treatment was quickly dampened by inflammatory response induced following TNFα administration, and the fact that most tumor cells resist killing by this cytokine. As a matter of fact, in several instances it may work as growth enhancer instead of a growth inhibitor. In this study, the research team found that MEK inhibitors increase the number of TNFα receptors on the cell surface (TNFR1), which leads to the delivery of a more potent and sustained cell death signal. IFN-gamma, a cytokine known to be crucial for anti-tumor immunity, further enhances the anti-tumor activity of MEK inhibitors and TNFα. Importantly, MEK inhibitors also considerably increases expression of TNFα and IFNγ target genes, which can lead to increase in anti-tumor immunity.

Whilst B-Raf or MEK inhibiots alone are effective but incomplete, the combination of BRAFi/MEKi and immune checkpoint inhibitors combines the hope for a fast, reliable and lasting response to therapy. Preclinical data supports this hypothesis. Treatment with MEKi led to acquisition of a novel vulnerability to TNF-alpha and IFNg-induced apoptosis in lung cancer cells that were refractory to MEKi killing and augmented cell cycle arrest. Amer A. Beg, Ph.D., senior member of the Immunology Department and Lung Cancer Center of Excellence at Moffitt and lead author of this study, explained: “MEK inhibitors alone do not provide strong overall response for this group of patients. This is why we deepened research further by investigating whether MEK inhibitors in combination with therapies known to increase expression of TNFα and gamma IFN would provide a better response. We discovered that adding a PD-1 immune checkpoint inhibitor with MEK inhibitors resulted in the strongest tumor regression in mice”. The researchers are planning further studies to combine MEK inhibitors with other immune therapies that provide strong expression of these cytokines in the tumor microenvironment, such as the nowadays famous CAR-T and adoptive T cell therapy approaches.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Xie M, Zheng H et al., Beg AA. Cancer Res. 2019 Jul 30.

Liu X, Hu J et al. Chen X. Cancers (Basel) 2019 Jul 3;11(7).

Kuske M et al. Pharmacol Res. 2018 Oct; 136:151-159.